Table 2
Selected proteins from the AD susceptibility network shown in Figure Figure88
| Name | Description |
|---|---|
| Cell-cell and cell-ECM adhesions, cytoskeletal coupling, and the associated cell signaling | |
| ANK-1 | Ankyrin-1. Attaches integral membrane proteins to cytoskeletal elements; binds to the cytoskeletal proteins fodrin, tubulin, vimentin, and desmin. |
| CDH23 | Cadherin-23. Unconventional cadherin. Expressed in the sensory neuroepithelium. Mutated in the Usher syndrome (deafness) and nonsyndromic autosomal recessive deafness DFNB12. |
| DSG2 | CDHF5 / Cadherin family member 5. Desmosomal cadherin. Involved in the interaction of plaque proteins and intermediate filaments mediating cell-cell adhesion. |
| CD2AP | CMS / Mesenchyme-to-epithelium transition protein with SH3 domains 1. An adapter/scaffolding protein connecting membrane proteins and the actin cytoskeleton. In collaboration with CBL-C, modulates the rate of RET turnover and may act as regulatory checkpoint that limits the potency of GDNF on neuronal survival. May play a role in receptor clustering and cytoskeletal polarity in the immunological synapse. |
| CD33 | Putative adhesion molecule. May act as an inhibitory receptor upon ligand induced tyrosine phosphorylation by recruiting cytoplasmic phosphatase(s) via their SH2 domain(s) that block signal transduction through dephosphorylation of signaling molecules. Induces apoptosis in acute myeloid leukemia (in vitro). |
| EPHA1 | EPH, EPHT, EPHT1 / Ephrin type-A receptor 1. Receptor tyrosine kinase. Binds promiscuously membrane-bound ephrin-A family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. Upon activation by EFNA1 induces cell attachment to the extracellular matrix, inhibiting cell spreading and motility. Plays a role in angiogenesis and regulates cell proliferation. May play a role in apoptosis. |
| APP | Amyloid-beta precursor protein. Functions as a cell surface receptor and performs physiological functions on the surface of neurons related to neurite growth, neuronal adhesion, axonogenesis, and synaptogenesis. Involved in cell mobility and regulation of transcription. Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis and oxidative stress through copper ion reduction. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. |
| Presenilin1 (PSEN1) | Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of calcium influx or apoptosis, cleaves E-cadherin, promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin. |
| SERPINF2 | A potent and specific plasmin inhibitor. Inhibits the E-cadherin processing and ensuing dissolution of cell-cell adhesions by the plasminogen activator/plasmin system, thereby inhibiting invasion and metastasis in cancer cells. |
| Proliferation-and-migration related signaling | |
| SERPINF1 | Pigment epithelium-derived factor (PEDF). A neurotrophic factor. Promotes differentiation of retinoblastoma and other tumor cells of neuronal origin by promoting neurite outgrowth with concomitant upregulation of neurofilament proteins. Markedly promotes adhesion to collagen-I and inhibits invasiveness. Induces growth arrest and tumor differentiation to a less malignant phenotype. Treatment of endothelial cells with SERPINF1/PEDF significantly increases gamma-secretase activity, which is associated with upregulation of Presenelin 1 and its translocation from the perinuclear region to the plasma membrane. Actions of PEDF are mediated by JNK and p38 MAPK signaling pathways. Activation of the PEDF receptor (PEDFR), which is expressed in many cell types, suppresses NF-kB signaling and expression of pro-migratory genes. Hypoxia is associated with reduced levels of PEDF [134]. |
| PTK2B | FAK2, PYK2, RAFTK / Protein-tyrosine kinase 2-beta / Focal adhesion kinase 2. Non-receptor protein-tyrosine kinase that regulates reorganization of the actin cytoskeleton, cell polarization, cell migration, adhesion, spreading and bone remodeling. Required for normal macrophage polarization and migration towards sites of inflammation. Regulates cytoskeleton rearrangement and cell spreading in T-cells, and contributes to the regulation of T-cell responses. Functions in signaling downstream of integrin and collagen receptors, immune receptors, G-protein coupled receptors (GPCR), cytokine, chemokine and growth factor receptors, and mediates responses to cellular stress. Regulates numerous signaling pathways. Promotes activation of the phosphatidylinositol 3-kinase (PI3K) and AKT1 signaling cascade as well as the MAP kinase signaling cascade, including activation of MAPK1/ERK2, MAPK3/ERK1 and MAPK8/JNK1. Aberrant PTK2B/PYK2 expression may play a role in cancer cell proliferation, migration and invasion, in tumor formation and metastasis. Elevated PTK2B/PYK2 expression is seen in gliomas, hepatocellular carcinoma, lung cancer and breast cancer. |
| INPP5D | SHIP-1. Phosphatidylinositol (PtdIns) phosphatase. Specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K pathways. Acts as a negative regulator of B-cell antigen receptor signaling. Acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. Key regulator of neutrophil migration, by governing the formation of the leading edge and polarization required for chemotaxis. Involved in the control of cell-cell junctions, CD32a signaling in neutrophils and modulation of EGF-induced phospholipase C activity. Mediates the activin/TGF-beta-induced apoptosis through its SMAD-dependent expression. |
| Ras signaling and migration | |
| RIN3 | Ras and Rab interactor 3. A Ras effector and RAB5-directed guanine nucleotide exchange factor (GEF), which is highly expressed and enriched in human mast cells. Stimulation of the receptor tyrosine kinase c-KIT by Stem Cell Factor (SCF) triggers activation of Ras and its downstream effectors. SCF activation of c-KIT is critical for recruiting mast cells to sites of infection or injury. RIN3 functions as an inhibitor of mast cell migration toward SCF, via a mechanism involving c-KIT internalization. RIN1 isoform is highly expressed in mature forebrain neurons and disruption of the RIN1 gene results in elevated LTP and enhanced aversive memories in mutant mice. RIN1 is a regulator of cell adhesion and migration. RIN1 regulates cell migration by coupling endocytosis of activated receptor tyrosine kinases, which is controlled by RAB5 GTPases, and cytoskeletal remodeling, which is controlled by ABL tyrosine kinases [135]. |
| Stress / mitogenic signaling, NF-kB activation, cytoskeletal dynamics, cell adhesion, and motility | |
| MAP3K2 | Mitogen-activated protein kinase kinase kinase 2 / MEKK2. Integrates stress and mitogenic signals to the activation of NF-kB, JNKs, p38, and ERK5 pathways. Directly phosphorylates and activates stress-activated protein kinases (SAPK/JNKs) and I-kappa-B kinases (IKKs). Promotes motility and invasiveness in cancer cells, in part through control of focal adhesion stability [136]. |
| Regulation of glycolysis | |
| PFKFB2 | 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2. PFKFB (isoforms PFKFB1-4) sets the pace of glycolysis in cells by controlling intracellular levels of fructose 2,6-bisphosphate (F2,6BP). F2,6BP is the most potent allosteric activator of PFK-1 (6-phosphofructo-1-kinase), which catalyzes the essentially irreversible, commitment step in the glycolytic pathway. F2,6BP allows PFK-1 to bypass the inhibition by ATP, thereby permitting cells to maintain high rates of glycolysis even at physiological ATP concentrations. Induced by hypoxia, hypoxia mimics, growth factors, and hormones. Overexpressed in a large variety of cancers. Required for cell transformation by oncogenic Ras [137]. |
| Regulation of oxidative phosphorylation | |
| MEF2C | Myocyte-specific enhancer factor 2C. Transcriptional factor MEF2 (isoforms MEF2A/B/C/D). MEF2A/C/D isoforms are highly expressed in the brain, where MEF2s regulate neuronal development, synaptic plasticity, activity-dependent survival, learning and memory. MEF2C facilitates learning and memory by negative regulation of synapse numbers and function. In stimulated mast cells, MEF2C isoform regulates c-JUN expression. MEF2D isoform was shown to act as a mitochondrial transcription factor that regulates expression of the mtDNA-encoded NADH dehydrogenase 6 (ND6), an essential component of complex I, whose insufficiency leads to a severe disruption of complex I structure and impairment of oxidative phosphorylation. MEF2D and ND6 protein levels are greatly reduced in brain mitochondria of human Parkinson's disease (PD) patients and MPTP-treated mice modeling PD. An average 50% reduction of the mtDNA ND6 transcripts has been also detected in AD brains. Ablation of MEF2A isoform in mice disrupts mitochondrial and cyto-architectural integrity in the post-natal heart, leading to sudden death [138]. MEF2 mediates TGF-beta-induced EMT in hepatocellular carcinoma, promoting migration and invasion of cancer cells. MEF2 synergizes with activated Notch in Drosophila to promote hyperproliferative and invasive cellular phenotypes via JNK activation. |
| Inflammation | |
| TREM1 | Triggering receptor expressed on myeloid cells 1 (ACUTE INFLAMMATION) Stimulates neutrophil- and monocyte-mediated inflammatory responses. Triggers release of pro-inflammatory chemokines and cytokines, as well as increased surface expression of cell activation markers. Amplifier of inflammatory responses triggered by bacterial and fungal infections and is a crucial mediator of septic shock. Strongly expressed in acute inflammatory lesions caused by bacteria and fungi. |
| TREM2 | Triggering receptor expressed on myeloid cells 2 (CHRONIC INFLAMMATION) May have a role in chronic inflammation, stimulating production of constitutive rather than inflammatory chemokines and cytokines. Triggers activation of the immune responses in macrophages and dendritic cells. Mutated in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL). PLOSL is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. |